Live vector delivery systems can effectively target mucosal inductive sites for the efficacious delivery of vaccine antigens to induce both mucosal and systemic immunity. Typically, attenuated Salmonella vectors, adept at delivering vaccines to the Peyer's patches (PP) of the small intestine, elicit T helper (Th) 1 cell (IFN-g-dependent) immune responses to resolve this intracellular pathogen. However, our studies have shown that we can obtain elevated Th2 cell (IL-4-dependent) immune responses, followed by a delayed onset of Th1 cells, to colonization factor antigen I (CFA/I) from human enterotoxigenic Escherichia coli (ETEC) when expressed on the Salmonella cell surface (strain H696). Subsequent studies revealed that proinflammatory cytokine production and inflammatory cell infiltrates in the PP are attenuated. Such findings led us to question whether this is an anti-inflammatory vaccine. Consequently, mice orally immunized with Salmonella-CFA/l prevented proteolipidpeptide 139-151-mediated experimental autoimmune encephalitis (EAE) in an antigen-independent fashion as evidenced by reduced disease severity and complete recovery, in fact, minimal leukocyte infiltration into the central nervous system was observed. In contrast, S JL/J mice orally immunized with the Salmonella control strain or PBS showed progressive EAE and no recovery. Such evidence indicates that this vaccine functions systemically and nonspecifically by attenuating the innate and adaptive immune systems. To understand the mechanisms of action, we propose three Specific Aims. Studies in Specific Aim 1 will determine whether Salmonella-CFA/l suppresses or bypasses inflammation via induction of regulatory T cells or plasmacytoid dendritic cells. Studies in Specific Aim 2 will determine how Salmonella-CFA/l suppresses EAE, and whether this vaccine can be therapeutic for ongoing EAE. Studies also will determine whether protection can be adoptively transferred. Studies in Specific Aim 3 will determine whether expression of CFA/I fimbriae can redirect virulent Salmonella to alter its pathogenicity. Thus, from these studies we will learn the specific mechanisms induced by this anti-inflammatory vaccine.